U.S. patent application number 10/643649 was filed with the patent office on 2005-02-24 for methods and apparatus for treatment of aneurysmal tissue.
This patent application is currently assigned to Medtronic AVE, Inc.. Invention is credited to Brin, David S., Chu, Jack, Doig, Scott.
Application Number | 20050043786 10/643649 |
Document ID | / |
Family ID | 34063464 |
Filed Date | 2005-02-24 |
United States Patent
Application |
20050043786 |
Kind Code |
A1 |
Chu, Jack ; et al. |
February 24, 2005 |
Methods and apparatus for treatment of aneurysmal tissue
Abstract
Methods and apparatus for aiding aneurysm repair are provided.
Such apparatus is constructed to support or bolster the aneurysmal
site initially, while contracting if the aneurysmal site shrinks or
contracts. The apparatus also supplies a pharmaceutical agent to
aid in healing the surrounding aneurysmal tissue. The apparatus may
comprise a drug eluting polymer or may have a passive coating which
can be selectively deployed by adding an activation agent after
deployment. The device can be used alone or in conjunction with a
AAA stent graft that isolates the aneurysmal sac from the vascular
system.
Inventors: |
Chu, Jack; (Santa Rosa,
CA) ; Doig, Scott; (Santa Rosa, CA) ; Brin,
David S.; (Santa Rosa, CA) |
Correspondence
Address: |
PATENT COUNSEL
MEDTRONIC AVE, INC.
3576 Unocal Place
Santa Rosa
CA
95403
US
|
Assignee: |
Medtronic AVE, Inc.
|
Family ID: |
34063464 |
Appl. No.: |
10/643649 |
Filed: |
August 18, 2003 |
Current U.S.
Class: |
623/1.42 ;
623/1.2; 623/1.22 |
Current CPC
Class: |
A61F 2250/0067 20130101;
A61F 2/88 20130101 |
Class at
Publication: |
623/001.42 ;
623/001.2; 623/001.22 |
International
Class: |
A61F 002/06 |
Claims
What is claimed is:
1. An intravascular treatment device, comprising: a stent locatable
interior of an aneurysmal site in a blood vessel; wherein the stent
supports the aneurysmal site upon deployment, contracts when the
aneurysmal site contracts, and comprises at least one therapeutic
agent.
2. The device of claim 1, wherein the stent has a helical
configuration.
3. The device of claim 2, wherein the stent comprises at least one
helix.
4. The device of claim 3, wherein the stent comprises two
helices.
5. The device of claim 4, wherein the stent comprises three
helices.
6. The device of claim 1, wherein the stent is self-expandable.
7. The treatment device of claim 1, wherein the stent comprises a
polymer.
8. The treatment device of claim 7, wherein the polymer is
biodegradable.
9. The treatment device of claim 8, wherein the polymer is
cellulose acetate, cellulose acetate proprionate, cellulose
butyrate, cellulose proprionate, cellulose valerate, cumaroneindene
polymer, dibutylaminohydroxypropyl ether, ethyl cellulose,
ethylene-vinyl acetate copolymer, glycerol distearate,
hydorxypropylmethyl cellulose phthalate, 2-methyl-5-vinylpyridine
methylate-methacrylic acid copolymer, polyamino acids,
polyanhydrides, polycaprolactone, polybutidiene, polyesters,
aliphatic polyesters, polyhydroxybutyric acid, polymethyl
methacrylate, polymethacrylic acid ester, polyolesters,
polysaccharides, such as alginic acid, chitin, chitosan,
chondroitin, dextrin, dextran, proteins such as albumin, casein,
collagen, gelatin, fibrin, fibrinogen, hemoglobin, transfferrin,
vinylchloride-propylene-vinylacetate copolymer, palmitic acid,
stearic acid, behenic acid, aliphatic polyesters, hyaluronic acid,
heparin, kearatin sulfate, starch, polystyrene, polyvinyl acetal
diethylamino acetate, polyvinyl acetate, polyvinyl alcohol,
polyvinyl butyral, polyvinyl formal, poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(orthoglycolides), poly(orthoglycolide acrylates), poly(ortho
acrylates), poly(hydroxybutyrate), poly(alkylcarbonate) and
poly(orthoesters), poly(hydroxyvaleric acid), polydioxanone,
poly(ethylene terephthalate), poly(malic acid), poly(tartronic
acid), polyanhydrides, polyphosphazenes, or blends, admixtures, or
co-polymers thereof.
10. The treatment device of claim 8, wherein the therapeutic agent
is covalently linked to the polymer.
11. The treatment device of claim 7, wherein the polymer is not
biodegradable.
12. The treatment device of claim 11, wherein the polymer is
poly(ethylene-vinyl acetate) ("EVA") copolymers, silicone rubber,
polyamides (nylon 6,6), polyurethane, poly(ester urethanes),
poly(ether urethanes), poly(ester-urea), polypropylene,
polyethylene, polycarbonate, PEEK, polytetrafluoroethylene,
expanded polytetrafluoroethylene, polyethylene teraphthalate
(Dacron), polypropylene or blends, admixtures, or co-polymers
thereof.
13. The treatment device of claim 7, wherein the polymer is a
pH-sensitive polymer.
14. The treatment device of claim 13, wherein the pH-sensitive
polymer is poly(acrylic acid) or its derivatives; poly(acrylic
acid); poly(methyl acrylic acid), copolymers of poly(acrylic acid)
and acrylmonomers; cellulose acetate phthalate;
hydroxypropylmethylcellulose phthalate; hydroxypropyl
methylcellulose acetate succinate; cellulose acetate trimellilate;
or chitosan.
15. The treatment device of claim 7, wherein the polymer is a
temperature-sensitive polymer.
16. The treatment device of claim 15, wherein the
temperature-sensitive polymer is
poly(N-methyl-N-n-propylacrylamide; poly(N-n-propylacrylamide)- ;
poly(N-methyl-N-isopropylacrylamide);
poly(N-n-propylmethacrylamide; poly(N-isopropylacrylamide);
poly(N,n-diethylacrylamide); poly(N-isopropylmethacrylamide);
poly(N-cyclopropylacrylamide); poly(N-ethylmethyacrylamide);
poly(N-methyl-N-ethylacrylamide);
poly(N-cyclopropylmethacrylamide); poly(N-ethylacrylamide);
hydroxypropyl cellulose; methyl cellulose; hydroxypropylmethyl
cellulose; and ethylhydroxyethyl cellulose, or pluronics F-127;
L-122; L-92; L-81; or L-61 or copolymers thereof.
17. The treatment device of claim 1, wherein the stent comprises
metal.
18. The treatment device of claim 19, wherein the metal is a metal
alloy.
19. The treatment device of claim 18, wherein the metal alloy is
NiTi.
20. The treatment device of claim 1, wherein the therapeutic agent
is at least one of a metalloproteinase inhibitor, cyclooxygenase-2
inhibitor, anti-adhesion molecule, tetracycline-related compound,
beta blocker, NSAID, or an angiotensin converting enzyme
inhibitor.
21. The treatment device of claim 20, wherein the cyclooxygenase-2
inhibitor is Celecoxib, Rofecoxib, Parecoxib, green tea, ginger,
turmeric, chamomile, Chinese gold-thread, barberry, Baikal
skullcap, Japanese knotweed, rosemary, hops, feverfew, oregano,
piroxican, mefenamic acid, meloxican, nimesulide, diclofenac,
MF-tricyclide, raldecoxide, nambumetone, naproxen, herbimycin-A, or
etoicoxib.
22. The treatment device of claim 20, wherein the anti-adhesion
molecule is anti-CD18 monoclonal antibody.
23. The treatment device of claim 20, wherein the
tetracycline-related compound is doxycycline, aureomycin,
chloromycin, 4-dedimethylaminotetrac- ycline,
4-dedimethylamino-5-oxytetracycline, 4-dedimethylamino-7-chlorotet-
racycline, 4-hydroxy-4-dedimethylaminotetracycline, 5 a,
6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-12a-d- eoxytetracycline,
6-.alpha.-deoxy-5-hydroxy-4-dedimethylaminotetracycline,
tetracyclinonitrile, 6-.alpha.-benzylthiomethylenetetracycline,
6-fluoro-6-demethyltetracycline, or
11-.alpha.-chlorotetracycline.
24. The treatment device of claim 20, wherein the beta blocker is
acebutolol, atenolol, betaxolol, bisoprolol, carteolol, carvedilol,
esmolol, labetolol, metoprolol, nadolol, penbutolol, pindolol,
propranolol, or timolol.
25. The treatment device of claim 20, wherein the NSAID is
indomethacin, ketorolac, ibuprofen or aspirin.
26. The treatment device of claim 20, wherein the angiotensin
converting enzyme inhibitor is captopril or lisinopril.
27. The treatment device of claim 20, wherein the angiotensin
converting enzyme inhibitor is enalaprilat, fosinoprilat,
benazeprilat, trandolaprilat, quinaprilat, ramiprilat, moexiprilat,
or perindoprilat.
28. The treatment device of claim 7, wherein the therapeutic agent
is contained in a microsphere associated with the polymer.
29. The treatment device of claim 28, wherein in microsphere is
about 50 nm to 500 .mu.m in size.
30. The treatment device of claim 29, wherein the spray is prepared
from microspheres of about 0.1 .mu.m to about 100 .mu.m in
size.
31. The treatment device of claim 1, wherein the therapeutic agent
is applied as a coating to the stent.
32. The treatment device of claim 31, wherein the coating is
applied as a paste, thread, film or spray.
33. The treatment device of claim 32, wherein the film is from 10
.mu.m to 5 mm thick.
34. The treatment device of claim 31, further comprising a second
coating deposed over the therapeutic coating.
35. The treatment device of claim 34, wherein there are at least
two therapeutic coatings, wherein each therapeutic coating is
separated by a second coating.
36. The treatment device of claim 31, wherein the coating is a
biodegradable coating.
37. The treatment device of claim 36, wherein the polymer is
cellulose acetate, cellulose acetate proprionate, cellulose
butyrate, cellulose proprionate, cellulose valerate, cumaroneindene
polymer, dibutylaminohydroxypropyl ether, ethyl cellulose,
ethylene-vinyl acetate copolymer, glycerol distearate,
hydorxypropylmethyl cellulose phthalate, 2-methyl-5-vinylpyridine
methylate-methacrylic acid copolymer, polyamino acids,
polyanhydrides, polycaprolactone, polybutidiene, polyesters,
aliphatic polyesters, polyhydroxybutyric acid, polymethyl
methacrylate, polymethacrylic acid ester, polyolesters,
polysaccharides, such as alginic acid, chitin, chitosan,
chondroitin, dextrin, dextran, proteins such as albumin, casein,
collagen, gelatin, fibrin, fibrinogen, hemoglobin, transfferrin,
vinylchloride-propylene-vinylacetate copolymer, palmitic acid,
stearic acid, behenic acid, aliphatic polyesters, hyaluronic acid,
heparin, kearatin sulfate, starch, polystyrene, polyvinyl acetal
diethylamino acetate, polyvinyl acetate, polyvinyl alcohol,
polyvinyl butyral, polyvinyl formal, poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(orthoglycolides), poly(orthoglycolide acrylates), poly(ortho
acrylates), poly(hydroxybutyrate), poly(alkylcarbonate) and
poly(orthoesters), poly(hydroxyvaleric acid), polydioxanone,
poly(ethylene terephthalate), poly(malic acid), poly(tartronic
acid), polyanhydrides, polyphosphazenes, or blends, admixtures, or
co-polymers thereof.
38. The treatment device of claim 31, wherein the coating is a time
release coating.
39. The treatment device of claim 38, wherein the time release
coating releases from about 1% to about 25% of the therapeutic
agent within 10 days after deployment.
40. The treatment device of claim 1, wherein the stent is formed by
casting or laser cutting.
41. The treatment device of claim 1, wherein the stent is deployed
by a catheter.
42. A method of treating an aneurysm comprising deploying the
device of claim 1 in an aneurysmal site.
43. An intravascular treatment device, comprising a helical stent
locatable interior of an aneurysmal site in a blood vessel; wherein
the stent supports the aneurysmal site upon deployment, contracts
when the aneurysmal site contracts, and comprises at least one
therapeutic agent.
44. The treatment device of claim 43, wherein the stent is
biodegradable.
45. The treatment device of claim 44, wherein the stent comprises
poly(orthoester).
46. The method of treating an aneurysm as in claim 42 further
comprising deploying a stent graft to exclude the aneurysm the a
substantial portion of device of claim 1 is disposed between the
stent graft and the wall of the aneurysm.
47. The method of treating an aneurysm as in claim 46, wherein said
therapeutic agent is inactive until it comes in contact with an
activating agent.
Description
FIELD OF THE INVENTION
[0001] The field of the invention is the treatment of vascular
abnormalities.
BACKGROUND OF THE INVENTION
[0002] Aortic aneurysms pose a significant medical problem for the
general population. Aneurysms within the aorta presently affect
between two and seven percent of the general population and the
rate of incidence appears to be increasing. This form of
atherosclerotic vascular disease (hardening of the arteries) is
characterized by degeneration in the arterial wall in which the
wall weakens and balloons outward by thinning. Generally, until the
affected artery is removed or bypassed, a patient with an aortic
aneurysm must live with the threat of aortic aneurysm rupture and
death.
[0003] One clinical approach for patients with an aortic aneurysm
is aneurysm repair by endovascular grafting. Endovascular grafting
involves the transluminal placement of a prosthetic arterial stent
in the endoluminal position (within the lumen of the artery). To
prevent rupture of the aneurysm, a stent graft of tubular
construction is introduced into the aneurysmal blood vessel,
typically from a remote location through a catheter introduced into
a major blood vessel in the leg.
[0004] Despite the effectiveness of endovascular grafting, once the
aneurysmal site is bypassed, the aneurysm remains. The aortic
tissue can continue to degenerate such that the aneurysm increases
in size due to thinning of the medial connective tissue
architecture of the aorta and loss of elastin. Thus there is a
desire in the art to achieve a greater success of aneurysm repair
and healing. The present invention satisfies this need in the
art.
SUMMARY OF THE INVENTION
[0005] Embodiments according to the present invention address the
problem of aneurysm repair, particularly the problem of continued
breakdown of aortic aneurysmal tissue. A consequence of such
continued breakdown is rupture of the aneurysm. Embodiments
according to the present invention provide an apparatus of a
construction capable of supporting or bolstering the aneurysmal
site initially, while contracting if the aneurysmal site shrinks or
contracts. The apparatus also supplies a pharmaceutical agent to
aid in healing the surrounding aneurysmal tissue. One embodiment
according to the invention includes methods of treating an aneurysm
by deploying the apparatus in an aneurysmal site.
[0006] Thus, in one embodiment according to the invention there is
provided an intravascular treatment device, comprising a
contractable stent locatable adjacent to an aneurysmal site where
the stent includes a therapeutic agent. In some embodiments of the
invention, the stent is biodegradable and in some aspects of this
embodiment, the therapeutic agent is formulated as part of the
biodegradable stent. In other embodiments, the stent may or may not
be biodegradable and the therapeutic agent is formulated as a
coating, film or other compound applied to the stent. Therapeutic
agents that can be used according to the present invention include
matrix metalloproteinase inhibitors, cyclooxygenase-2 inhibitors,
anti-adhesion molecules, tetracycline-related compounds, beta
blockers, NSAIDs, anti inflammation drugs angiotensin converting
enzyme inhibitors or the like.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a schematic view of a human aortal aneurysm.
[0008] FIG. 2 is a partial sectional view of a descending aorta
with a stent placed therein.
[0009] FIG. 3A and FIG. 3B show embodiments of a stent according to
the present invention.
[0010] FIG. 4A shows a delivery catheter for a ribbon-type stent.
FIG. 4B shows a delivery catheter for a wire-type stent.
[0011] FIGS. 5A through 5D show progressive idealized views of a
self-guiding delivery catheter from which a ribbon or wire type
stent or a similar extrusion can be delivered.
[0012] FIGS. 6A and 6B show a ribbon stent and its cross sectional
configurations.
[0013] FIGS. 7A and 7B show a stent cross section configured in a
layer structure.
DETAILED DESCRIPTION
[0014] Reference will now be made in detail to exemplary
embodiments according to the invention.
[0015] Methods and apparatus for stabilizing and treating an
aneurysmal site include implanting of a contractable endovascular
stent that delivers a bioactive amount of one or more therapeutic
agents to the aneurysmal site. In contrast to a stent graft, a
stent when inserted and deployed in a vessel acts as a prosthesis
to maintain the vessel open. The stent typically has the form of an
open-ended tubular element and most frequently is configured to
enable its expansion from a small outside diameter which is
sufficiently small to allow the stent to traverse the vessel to
reach a site where it is to be deployed, to a large outside
diameter sufficiently large to engage the inner lining of the
vessel for retention at the site.
[0016] The customary procedure is to install a stent at an
occlusion site at the time of or shortly after an angioplasty or
other procedure is performed. The stent is deployed by, e.g.,
radial expansion under outwardly-directed radial pressure exerted
by active inflation of the balloon of a balloon catheter on which
the stent is mounted. In other instances, passive spring
characteristics of a pre-formed stent operate to deploy the device.
The stent is thus expanded to engage the inner lining or
inwardly-facing surface of the vessel wall with sufficient
resilience to allow some contraction from full expansion size of
the stent but also with sufficient stiffness so that the stent
largely resists the natural recoil of the vessel wall--particularly
at the ends of the stent where it encounters healthy vessel
tissue.
[0017] The stent is implanted in an individual in a typical manner,
where the stent acts as a delivery vehicle to deliver one or more
therapeutic agents to the aneurysmal site.
[0018] Referring initially to FIG. 1, there is shown generally an
aneurysmal blood vessel 02; in particular, there is an aneurysm of
the aorta 12, such that the blood vessel wall 04 is enlarged at an
aneurysmal site 14. The aneurysmal site 14 forms an aneurysmal
bulge or sac 18. If left untreated, the aneurysmal sac 18 may
continue to deteriorate, weaken, increase in size, and eventually
tear or burst.
[0019] FIG. 2 shows the transluminal placement of a prosthetic
arterial stent 30, positioned in a blood vessel 10, in this
embodiment, an abdominal aorta 12. The prosthetic arterial stent
spans, within the aorta 12, an aneurysmal portion 14 of the aorta
12. The aneurysmal portion 14 is formed due to a bulging of the
aorta wall 16, in a location where the strength and resiliency or
the aorta wall 16 is weakened. As a result, an aneurysmal sac 18 is
formed of distended vessel wall tissue. The stent 30 is positioned
spanning the sac 18 adjacent to inner wall 16.
[0020] The placement of the stent 30 in the aorta 12 is a technique
well known to those skilled in the art, and essentially includes
opening a blood vessel in the leg or other remote location and
inserting the stent 30 contained inside a catheter (not shown) into
the blood vessel. The catheter/stent combination is tracked through
the remote vessel until the stent 30 is deployed in a position that
spans the aneurysmal portion 14 of aorta 12.
[0021] FIGS. 3A and 3B show two embodiments of stents according to
the present invention, both having a single helical configuration.
FIG. 3A shows a stent with a ribbon-like configuration, while the
stent in FIG. 3B has a wire-like configuration. In addition to
single helices, double-, triple- and multiple-helix configurations
are also possible. The stents according to the present invention
can be manufactured by, for example, laser cutting, casting or
extruding and can also be manufactured in multiple sub-section
pieces.
[0022] Stents are designed to be deployed and expanded in different
ways. A stent can be designed to self expand upon release from its
delivery system, or it may require application of a radial force
through the delivery system to expand the stent to the desired
diameter or it can be deployed in a way to introduce radial force
by itself (FIG. 5). The helical ribbon-type or wire-type stents of
the present invention typically are self-expanding due to their
spring-like configuration. Self-expanding stents are compressed
prior to insertion into the delivery device and released by the
practitioner when correctly positioned at the delivery site. FIG.
4A shows an open schematic cross section of a catheter delivery
device 40 illustrating a short section of a ribbon-type helical
stent 30a and a push rod 50 to be used to move the stent 30a out of
the catheter 40. After release, the stent self-expands to a
predetermined diameter and is held in place by expansion force of
the device against the interior wall of the vessel. FIG. 4B shows a
closed longitudinal view of a catheter delivering a wire-type
helical stent 30b according to the present invention.
[0023] Stents that require mechanical expansion by the surgeon are
commonly deployed by a balloon-type catheter. Once positioned
within the stricture, the stent is expanded in situ to a size
sufficient to fill the lumen. Various designs and other means of
expansion also have been developed for stent delivery. One
technique that is available for a metal core or a polymer based
stent is shown in the progression of FIGS. 5A to 5D. A self guiding
catheter 32 is guided into the aneurysmal section of the aorta. In
FIG. 5B the self guiding catheter 32 is positioned in the upper
portion of the aneurysmal sac, and the stiffening element (not
shown, but known person skilled in the art) of the self guiding
catheter is retracted causing the end of the catheter to make a
bend 33. A distal portion 34 of the stent 35 is shown being pushed
out of the catheter 32 in close proximity to the vessel wall. As
the stent 35 is pushed further out the catheter 32 may be rotated
so that the bend 33 directs the catheter portion being released
from the catheter toward the vessel wall progressively to reduce
the distance that the stent must expand before it reaches the
vessel wall and reduces the amount of stent 35 that is unsupported
as it is released from the catheter 32. FIGS. 5C and 5D show the
progressive creation of loops 36 of wire forming a helical
progression down the inside portion of the aneurysmal sac.
[0024] The stent itself may be biodegradable including a
therapeutic agent formulated therewith (i.e., embedded in the
biodegradable polymer or covalently bound to the biodegradable
polymer); alternatively, the stent can be either biodegradable or
non-biodegradable with the therapeutic agent formulated with a
compound that is used to coat or is otherwise applied to the
stent.
[0025] One example of the construction of a ribbon stent is shown
in FIGS. 6A and 6B. An upper portion of a ribbon type stent is
pictured. The cross sectional cut has been taken at the top portion
and FIG. 6B is a view from the direction of arrow 6B. FIG. 6B shows
a stent stiffening member 37, which may be positioned centered near
one end of the rectangular shape where the remaining cross section
is polymer or drug material 38 from which the drug intended for the
vessel wall elutes. The stiffening wire could be metal such as
nitinol or stainless steel or could be a shape memory polymer
(either biodegradable or non-biodegradable). While the position of
a single stiffening member 37 is shown at a top end of the ribbon
stent in FIG. 6B, alternately the stiffening member may be
positioned centered in the middle 37a or bottom end 37b of the
ribbon stent as shown by the dashed circles representing those
respective positions. Alternately, multiple stiffening elements can
be used simultaneously to improve the outward radial force and
apposition between the outside surface of the stent and the inside
wall of sloped portions of the aneurysmal sac. The elements can
remain separate or can be interconnected in a ribbon type mesh.
[0026] When using a ribbon shaped stent as herein described the
drug eluting/delivery characteristics of the stent can be modified
by layered construction along the long axis of the cross section of
the ribbon. Two examples of such layered construction are shown in
FIGS. 7A and 7B. In FIG. 7A, the flow of the blood stream 42 is
shown at the top while close apposition with the vessel wall 48 is
shown at the bottom. A release barrier layer 43 to minimize the
release of drug to the blood stream is the outside (top) layer
provided. The next layer is a drug in polymer layer 44 which acts
as a reservoir for the drug(s) to be released. The next layer is a
control barrier layer 45 which acts to control the release rate of
drug through that layer to the adjacent vessel wall 48. The arrows
46 show the direction of drug flow. The release barrier layer 43
may wrap around the ends to prevent drug from being released from
the ends of the drug in polymer layer 44. An alternate layer
configuration is shown in FIG. 7B. The flow of the blood stream 42
is again shown at the top while close apposition with the vessel
wall 48 is shown at the bottom. However in this configuration the
top layer is a release barrier layer 43, while any controls to
prevent release of the drug in the polymer in the this controlled
release drug in polymer layer 47 is formulated to provide its own
control profile for release of the drug from the polymer. Again the
arrows 46 show the direction of drug flow.
[0027] The stent and/or coating compound is adapted to exhibit a
combination of physical characteristics such as biocompatibility,
and, in some embodiments, biodegradability and bio-absorbability,
while providing a delivery vehicle for release of one or more
therapeutic agents that aid in the treatment of aneurysmal tissue.
The coating compound used is biocompatible such that it results in
no induction of inflammation or irritation when implanted, degraded
or absorbed.
[0028] Thus, the stent and/or coating according to the present
invention may be either biodegradable or non-biodegradable.
Representative examples of biodegradable compositions include
cellulose acetate, cellulose acetate proprionate, cellulose
butyrate, cellulose proprionate, cellulose valerate, cumaroneindene
polymer, dibutylaminohydroxypropyl ether, ethyl cellulose,
ethylene-vinyl acetate copolymer, glycerol distearate,
hydorxypropylmethyl cellulose phthalate, 2-methyl-5-vinylpyridine
methylate-methacrylic acid copolymer, polyamino acids,
polyanhydrides, polycaprolactone, polybutidiene, polyesters,
aliphatic polyesters, polyhydroxybutyric acid, polymethacrylic acid
ester, polyolesters, polysaccharides (such as alginic acid, chitin,
chitosan, chondroitin, dextrin or dextran), proteins (such as
albumin, casein, collagen, gelatin, fibrin, fibrinogen, hemoglobin,
or transferring), vinylchloride-propylene-vinylacetate copolymer,
palmitic acid, stearic acid, behenic acid, aliphatic polyesters,
hyaluronic acid, heparin, kearatin sulfate, starch, polystyrene,
polyvinyl acetal diethylamino acetate, polyvinyl acetate, polyvinyl
alcohol, polyvinyl butyral, polyvinyl formal, poly(D,L-lactide),
poly(D,L-lactide-co-glycolide), poly(glycolide),
poly(orthoglycolides), poly(orthoglycolide acrylates), poly(ortho
acrylates), poly(hydroxybutyrate), poly(alkylcarbonate),
poly(orthoesters), poly(hydroxyvaleric acid), polydioxanone,
poly(malic acid), poly(tartronic acid), polyanhydrides,
polyphosphazenes, and their copolymers.
[0029] Representative examples of non-degradable polymers include
polymethyl methacrylate, poly(ethylene-vinyl acetate) ("EVA")
copolymers, silicone rubber, polyamides (nylon 6,6), polyurethane,
poly(ester urethanes), poly(ether urethanes), poly(ester-urea),
polypropylene, polyethylene, polycarbonate, PEEK, poly(ethylene
terephthalate),(Dacron), polytetrafluoroethylene, expanded
polytetrafluoroethylene, polypropylene or their copolymers. The
stent can be made using nitinol, stainless steel with drug coatings
on the stent; or the stent can be made of biodegradable or
non-biodegradable polymers. In general, see U.S. Pat. No. 6,514,515
to Williams; U.S. Pat. No. 6,506,410 to Park, et al.; U.S. Pat. No.
6,531,154 to Mathiowitz, et al.; U.S. Pat. No. 6,344,035 to
Chudzik, et al.; U.S. Pat. No. 6,376,742 to Zdrahala, et al.; and
Griffith, L. A., Ann. N.Y. Acad. of Sciences, 961:83-95 (2002); and
Chaikof, et al, Ann. N.Y. Acad. of Sciences, 961:96-105 (2002).
[0030] Additionally, the polymers as described herein also can be
blended or copolymerized in various compositions as required.
[0031] The stents and/or polymeric coatings as discussed can be
fashioned with desired release characteristics and/or with specific
desired properties. For example, the polymeric coatings can be
liquid in the catheter and may be fashioned to solidify upon
exposure to a specific triggering event such as pH (FIG. 5).
Similarly, the polymer/drug may be liquid in the catheter. After
the polymer/drug is extruded from the catheter it solidifies upon
exposure to a specific triggering event such as pH and forms a
stent on the vessel wall. Representative examples of pH-sensitive
polymers include poly(acrylic acid) and its derivatives (including
for example, homopolymers such as poly(aminocarboxylic acid);
poly(acrylic acid); poly(methyl acrylic acid), copolymers of such
homopolymers, and copolymers of poly(acrylic acid) and
acrylmonomers such as those discussed above. Other pH sensitive
polymers include polysaccharides such as cellulose acetate
phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropyl
methylcellulose acetate succinate; cellulose acetate trimellilate;
and chitosan. Yet other pH sensitive polymers include any mixture
of a pH sensitive polymer and a water-soluble polymer.
[0032] Likewise, polymeric carriers can be fashioned that are
temperature sensitive. Representative examples of thermogelling
polymers and their gelatin temperature include homopolymers such as
poly(N-methyl-N-n-propyl- acrylamide)(19.8.degree. C.);
poly(N-n-propylacrylamide)(21.5.degree. C.);
poly(N-methyl-N-isopropylacrylamide)(22.3.degree. C.);
poly(N-n-propylmethacrylamide(28.0.degree. C.);
poly(N-isopropylacrylamid- e)(30.9.degree. C.);
poly(N,n-diethylacrylamide)(32.0.degree. C.);
poly(N-isopropylmethacrylamide)(44.0.degree. C.);
poly(N-cyclopropylacryl- amide)(45.5.degree. C.);
poly(N-ethylmethyacrylamide)(50.0.degree. C.);
poly(N-methyl-N-ethylacrylamide)(56.0.degree. C.);
poly(N-cyclopropylmethacrylamide)(59.0.degree. C.);
poly(N-ethylacrylamide)(72.0.degree. C.). Moreover, thermogelling
polymers may be made by preparing copolymers between (among)
monomers of the above, or by combining such homopolymers with other
water-soluble polymers such as acrylmonomers (e.g., acrylic acid
and derivatives thereof such as methylacrylic acid, acrylate and
derivatives thereof such as butyl methacrylate, acrylamide, and
N-n-butyl acrylamide).
[0033] Other representative examples of thermogelling polymers
include cellulose ether derivatives such as hydroxypropyl cellulose
(41.degree. C.); methyl cellulose (55.degree. C.);
hydroxypropylmethyl cellulose (66.degree. C.); and
ethylhydroxyethyl cellulose, and Pluronics such as F-127
(10-15.degree. C.); L-122 (19.degree. C.); L-92 (26.degree. C.);
L-81 (20.degree. C.); and L-61 (24.degree. C.).
[0034] The polymer(s) used may be obtained from various chemical
companies known to those with skill in the art. However, because of
the presence of unreacted monomers, low molecular weight oligomers,
catalysts, and other impurities, it may be desirable (and,
depending upon the materials used, may be necessary) to increase
the purity of the polymer used. The purification process yields
polymers of better-known, purer composition, and therefore
increases both the predictability and performance of the mechanical
characteristics of the coatings. The purification process will
depend on the polymer or polymers chosen. Generally, in the
purification process, the polymer is dissolved in a suitable
solvent. Suitable solvents include (but are not limited to)
methylene chloride, ethyl acetate; chloroform, and tetrahydrofuran.
The polymer solution usually is then mixed with a second material
that is miscible with the solvent, but in which the polymer is not
soluble, so that the polymer (but not appreciable quantities of
impurities or unreacted monomer) precipitates out of solution. For
example, a methylene chloride solution of the polymer may be mixed
with heptane, causing the polymer to fall out of solution. The
solvent mixture then is removed from the copolymer precipitate
using conventional techniques. For information regarding stents and
coatings, see U.S. Pat. No. 6,387,121 to Alt; U.S. Pat. No.
6,451,373 to Hossainy, et al.; and U.S. Pat. No. 6,364,903 to
Tseng, et al.
[0035] In selecting an appropriate therapeutic agent or agents, one
objective is to protect the aneurysmal blood vessel from further
destruction and/or promote healing. Generally, aneurysm results
from the invasion of the vessel wall by elastin-attacking proteins
that occur naturally in the body, but for unknown reasons begin to
congregate at certain blood vessel sites, attack the blood vessel
structure and cause inflammation of the vessel. Generally, a
plurality of enzymes, proteins and acids--all naturally
occurring--interact through specific biochemical pathways to form
elastin and/or collagen-attacking proteins or to promote the
attachment or absorption of elastin and/or collagen-attacking
proteins into the vessel wall. The elastin and/or
collagen-attacking proteins and the resulting breakdown of tissue
and inflammation are leading causes of aneurysm formation.
[0036] The therapeutic agents described provide intervention in the
aforementioned biochemical pathways and mechanisms, reduction in
the level of the individual components responsible for aneurysmal
growth, and elimination or limitation of the advance of the
aneurysmal event. In particular, therapeutic agents are provided,
alone or in combination, to address the inflammation- or
elastin-attacking compounds, that cause the transition of a blood
vessel from a healthy to an aneurysmal condition. The therapeutic
agent or agents are released over time in the aneurysmal location,
reducing the likelihood of further dilation and increasing the
likelihood of successful repair of the aneurysm.
[0037] The therapeutic agents described are those useful in
suppressing proteins known to occur in and contribute to aneurysmal
sites, reducing inflammation at the aneurysmal site, and reducing
the adherence of elastin and/or collagen-attacking proteins at the
aneurysmal site. For example one class of materials, matrix
metallproteinase (MMP) inhibitors, have been shown in some cases to
reduce such elastin-attacking proteins directly, or in other cases
indirectly by interfering with a precursor compound needed to
synthesize the elastin-attacking protein. Another class of
materials, NSAIDs, have demonstrated anti-inflammatory qualities
that reduce inflammation at the aneurysmal site, as well as an
ability to block MMP-9 formation. Further, yet another class of
agents, attachment inhibitors, prevents or reduces the attachment
or adherence of elastin-attacking proteins or inflammation-causing
compounds onto the vessel wall at the aneurysmal site. Thus, these
therapeutic agents and other such agents, alone or in combination,
when provided at an aneurysmal site directly affect or undermine
the underlying sequence of events leading to aneurysm formation and
progression.
[0038] One class of agents useful in this application are those
that block the formation of MMP-9 by interfering with naturally
occurring body processes which yield MMP-9 as a byproduct.
Cyclooxygenase-2 or "COX-2" is known to metabolize a fat in the
body known as arachidonic acid or AA, a naturally occurring omega-6
fatty acid found in nearly all cell membranes in humans.
Prostaglandin E2 (PGE2) is synthesized from the catalyzation of
COX-2 and arachidonic acid and, when PGE2 is taken up by
macrophages, it results in MMP-9 formation. Thus, if any of COX-2,
PGE2, or AA is suppressed, then MMP-9 formation will be suppressed.
Therefore, COX-2 inhibitors can be provided at the aneurysmal site.
Such COX-2 inhibitors include Celecoxib, Rofecoxib and Parecoxib,
all of which are available in pharmacological preparations.
Additionally, COX-2 inhibition has been demonstrated from
administration of herbs such as green tea, ginger, turmeric,
chamomile, Chinese gold-thread, barberry, Baikal skullcap, Japanese
knotweed, rosemary, hops, feverfew, and oregano; and other agents
such as piroxican, mefenamic acid, meloxican, nimesulide,
diclofenac, MF-tricyclide, raldecoxide, nambumetone, naproxen,
herbimycin-A, and etoicoxib, and it is specifically contemplated by
the present invention that such additional COX-2 inhibiting
materials may be formulated for use in an aneurysmal location.
[0039] In addition to inhibiting COX-2 formation, the generation of
elastin-attacking proteins may be limited by interfering with the
oxidation reaction between COX-2 and AA by reducing the capability
of AA to oxidize. It is known that certain NSAIDs provide this
function. For example, ketoralac tromethamine (Toradol) inhibits
synthesis of progstaglandins including PGE2. In addition, other
currently available NSAIDs, including indomethacin, ketorolac,
ibuprofen and aspirin, among others, reduce inflammation at the
aneurysmal site, limiting the ability of elastin attacking proteins
such as MMP-9 to enter into the cellular matrix of the blood vessel
and degrade elastin. Additionally, steroidal based
anti-inflammatories, such as methylprednisolone or dexamethasone
may be provided to reduce the inflammation at the aneurysmal
site.
[0040] Despite the presence of inhibitors of COX-2 or of the
oxidation reaction between COX-2 and AA; and/or despite the
presence of an anti-inflammatory to reduce irritation and swelling
of the blood vessel wall, MMP-9 may still be present in the blood
vessel. Therefore, another class of therapeutic agents useful in
this application is that which limits the ability of
elastin-attacking proteins to adhere to the blood vessel wall, such
as anti-adhesion molecules. Anti-adhesion molecules, such as
anti-CD 18 monoclonal antibody, limit the capability of leukocytes
that may have taken up MMP-9 to attach to the blood vessel wall,
thereby preventing MMP-9 from having the opportunity to enter into
the blood vessel cellular matrix and attack the elastin.
[0041] In addition, other therapeutic agents contemplated to be
used are tetracycline and related tetracycline-derivative
compounds. In using a tetracycline compound as a bioactive agent in
aneurysm treatment, the observed anti-aneurysmal effect appears to
be unrelated to and independent of any antimicrobial activity such
a compound might have. Accordingly, the tetracycline may be an
antimicrobial tetracycline compound, or it may be a tetracycline
analogue having little or no significant antimicrobial
activity.
[0042] Preferred antimicrobial tetracycline compounds include, for
example, tetracycline per se, as well as derivatives thereof.
Preferred derivatives include, for example, doxycycline, aureomycin
and chloromycin. If a tetracycline analogue having little or no
antimicrobial activity is to be employed, it is preferred that the
compound lack the dimethylamino group at position 4 of the ring
structure. Such chemically-modified tetracyclines include, for
example, 4-dedimethylaminotetracycline,
4-dedimethylamino-5-oxytetracycline,
4-dedimethylamino-7-chlorotetracycline,
4-hydroxy-4-dedimethylaminotetrac- ycline, 5 a,
6-anhydro-4-hydroxy-4-dedimethylaminotetracycline,
6-demethyl-6-deoxy-4-dedimethylaminotetracycline,
4-dedimethylamino-12a-d- eoxytetracycline, and
6.alpha.-deoxy-5-hydroxy-4-dedimethylaminotetracycli- ne. Also,
tetracyclines modified at the 2-carbon position to produce a
nitrile, e.g., tetracyclinonitrile, are useful as
non-antibacterial, anti-metalloproteinase agents. Further examples
of tetracyclines modified for reduced antimicrobial activity
include 6-.alpha.-benzylthiomethylenet- etracycline, the
mono-N-alkylated amide of tetracycline,
6-fluoro-6-demethyltetracycline, and
11-.alpha.-chlorotetracycline.
[0043] Among the advantages of devices according to the present
invention is that the therapeutic agent delivered, here the
tetracycline compound, is administered locally. In the case of
tetracycline, the amount delivered is an amount that has
substantially no antibacterial activity, but which is effective for
reducing pathology for inhibiting the undesirable consequences
associated with aneurysms in blood vessels. Alternatively, as noted
above, the tetracycline compound can have been modified chemically
to reduce or eliminate its antimicrobial properties. The use of
such modified tetracyclines may be preferred in some embodiments of
the present invention since they can be used at higher levels than
antimicrobial tetracyclines, while avoiding certain disadvantages,
such as the indiscriminate killing of beneficial microbes that
often accompanies the use of antimicrobial or antibacterial amounts
of such compounds.
[0044] Another class of therapeutic agent that finds utility in
inhibiting the progression of or inducing the regression of a
pre-existing aneurysm is beta blockers or beta adrenergic blocking
agents. Beta blockers are bioactive agents that reduce the symptoms
associated with hypertension, cardiac arrhythmias, angina pectoris,
migraine headaches, and other disorders related to the sympathetic
nervous system. Beta blockers also are often administered after
heart attacks to stabilize the heartbeat. Within the sympathetic
nervous system, beta-adrenergic receptors are located mainly in the
heart, lungs, kidneys and blood vessels. Beta-blockers compete with
the nerve-stimulated hormone epinephrine for these receptor sites
and thus interfere with the action of epinephrine, lowering blood
pressure and heart rate, stopping arrhythmias, and preventing
migraine headaches. Because it is also epinephrine that prepares
the body for "fight or flight", in stressful or fearful situations,
beta-blockers are sometimes used as anti-anxiety drugs, especially
for stage fright and the like. There are two main beta receptors,
beta 1 and beta 2. Some beta blockers are selective, such that they
selectively block beta 1 receptors. Beta 1 receptors are
responsible for the heart rate and strength of the heartbeat.
Nonselective beta blockers block both beta 1 and beta 2 receptors.
Beta 2 receptors are responsible for the function of smooth
muscle.
[0045] Beta blockers that may be used in the compounds and methods
according to the present invention include acebutolol, atenolol,
betaxolol, bisoprolol, carteolol, carvedilol, esmolol, labetolol,
metoprolol, nadolol, penbutolol, pindolol, propranolol, and
timolol, as well as other beta blockers known in the art.
[0046] In addition to therapeutic agents that inhibit elastases or
reduce inflammation are agents that inhibit formation of
angiotensin II, known as angiotensin converting enzyme (ACE)
inhibitors. ACE inhibitors are known to alter vascular wall
remodeling, and are used widely in the treatment of hypertension,
congestive heart failure, and other cardiovascular disorders. In
addition to ACE inhibitors' antihypertensive effects, these
compounds are recognized as having influence on connective tissue
remodeling after myocardial infarction or vascular wall injury.
[0047] ACE inhibitors prevent the generation of angiotensin-II, and
many of the effects of angiotensin-II involve activation of
cellular ATI receptors; thus, specific ATI receptor antagonists
have also been developed for clinical application. ACE is an
ectoenzyme and a glycoprotein with an apparent molecular weight of
170,000 Da. Human ACE contains 1277 amino acid residues and has two
homologous domains, each with a catalytic site and a region for
binding Zn.sup.+2. ACE has a large amino-terminal extracellular
domain and a 17-amino acid hydrophobic stretch that anchors the
ectoenzyme to the cell membrane. Circulating ACE represents
membrane ACE that has undergone proteolysis at the cell surface by
a sectretase.
[0048] ACE is a rather nonspecific enzyme and cleaves dipeptide
units from substrates with diverse amino acid sequences. Preferred
substrates have only one free carboxyl group in the
carboxyl-terminal amino acid, and proline must not be the
penultimate amino acid. ACE is identical to kininase II, which
inactivates bradkinin and other potent vasodilator peptides.
Although slow conversion of angiotensin I to angiontensin II occurs
in plasma, the very rapid metabolism that occurs in vivo is due
largely to the activity of membrane-bound ACE present on the
luminal aspect of the vascular system--thus, the localized delivery
of the ACE inhibitor contemplated by the present invention provides
a distinct advantage over prior art systemic modes of
administration.
[0049] Following the understanding of ACE, research focused on ACE
inhibiting substances to treat hypertension. The essential effect
of ACE inhibitors is to inhibit the conversion of relatively
inactive angiotensin I to the active angiotensin II. Thus, ACE
inhibitors attenuate or abolish responses to angiotensin I but not
to angiotensin II. In this regard, ACE inhibitors are highly
selective drugs. They do not interact directly with other
components of the angiotensin system, and the principal
pharmacological and clinical effects of ACE inhibitors seem to
arise from suppression of synthesis of angiotensin II.
Nevertheless, ACE is an enzyme with many substrates, and systemic
administration of ACE inhibitors may not be optimal.
[0050] Many ACE inhibitors have been synthesized: however, a
majority of ACE inhibitors are ester-containing prodrugs that are
100 to 1000 times less potent ACE inhibitors than the active
metabolites but have an increased bioavailability for oral
administration than the active molecules. Currently, twelve ACE
inhibitors are approved for used in the United States. In general,
ACE inhibitors differ with regard to three properties: (1) potency;
(2) whether ACE inhibition is due primarily to the drug itself or
to conversion of a prodrug to an active metabolite; and (3)
pharmacokinetics (i.e., the extent of absorption, effect of food on
absorption, plasma half-life, tissue distribution, and mechanisms
of elimination). For example, with the notable exceptions of
fosinopril and spirapril which display balanced elimination by the
liver and kidneys, ACE inhibitors are cleared predominantly by the
kidneys. Therefore, impaired renal function inhibits significantly
the plasma clearance of most ACE inhibitors, and dosages of such
ACE inhibitors should be reduced in patients with renal
impairment.
[0051] For systemic administration there is no compelling reason to
favor one ACE inhibitor over another, since all ACE inhibitors
effectively block the conversion of angiotensin I to angiontensin
II and all have similar therapeutic indications, adverse-effect
profiles and contraindications. However, there are preferred ACE
inhibitors for use in the present invention. ACE inhibitors differ
markedly in their activity and whether they are administered as a
prodrug, and this difference leads to the preferred
locally-delivered ACE inhibitors according to the present
invention.
[0052] One preferred ACE inhibitor is captopril (Capoten).
Captopril was the first ACE inhibitor to be marketed, and is a
potent ACE inhibitor with a Ki of 1.7 nM. Captopril is the only ACE
inhibitor approved for use in the United States that contains a
sulfhydryl moiety. Given orally, captopril is rapidly absorbed and
has a bioavailability of about 75%. Peak concentrations in plasma
occur within an hour, and the drug is cleared rapidly with a
half-life of approximately 2 hours. The oral dose of captopril
ranges from 6.25 to 150 mg two to three times daily, with 6.25 mg
three times daily and 25 mg twice daily being appropriate for the
initiation of therapy for heart failure and hypertension,
respectively.
[0053] Another preferred ACE inhibitor is lisinopril. Lisinopril
(Prinivil, Zestril) is a lysine analog of enalaprilat (the active
form of enalapril (described below)). Unlike enalapril, lisinopril
itself is active. In vitro, lisinopril is a slightly more potent
ACE inhibitor than is enalaprilat, and is slowly, variably, and
incompletely (about 30%) absorbed after oral administration; peak
concentrations in the plasma are achieved in about 7 hours.
Lisinopril is cleared as the intact compound in the kidney, and its
half-life in the plasma is about 12 hours. Lisinopril does not
accumulate in the tissues. The oral dosage of lisinopril ranges
from 5 to 40 mg daily (single or divided dosage), with 5 and 10 mg
daily being appropriate for the initiation of therapy for heart
failure and hypertension, respectively.
[0054] Enalapril (Vasotec) was the second ACE inhibitor approved in
the United States. However, because enalapril is a prodrug that is
not highly active and must be hydrolyzed by esterases in the liver
to produce enalaprilat, the active form, enalapril is not a
preferred ACE inhibitor of the present invention. Similarly,
fosinopril (Monopril), benazepril (Lotensin), fosinopril
(Monopril), trandolapril (Mavik), quinapril (Accupril), ramipril
(Altace), moexipirl (Univasc) and perindopril (Aceon) are all
prodrugs that require cleavage by hepatic esterases to transform
them into active, ACE-inhibiting forms, and are not preferred ACE
inhibitors. However, the active forms of these compounds (i.e., the
compounds that result from the prodrugs being converted by hepatic
esterases)--namely, enalaprilat (Vasotec injection), fosinoprilat,
benazeprilat, trandolaprilat, quinaprilat, ramiprilat, moexiprilat,
and perindoprilat--are suitable for use, and because of the
localized drug delivery, the bioavailability issues that affect the
oral administration of the active forms of these agents are
moot.
[0055] The maximal dosage of the therapeutic to be administered is
the highest dosage that effectively inhibits elastolytic,
inflammatory or other aneurysmal activity, but does not cause
undesirable or intolerable side effects. The dosage of the
therapeutic agent or agents used will vary depending on properties
of the coating, including its time-release properties, whether the
coating is itself biodegradable, and other properties. Also, the
dosage of the therapeutic agent or agents used will vary depending
on the potency, pathways of metabolism, extent of absorption,
half-life, and mechanisms of elimination of the therapeutic agent
itself. In any event, the practitioner is guided by skill and
knowledge in the field, and embodiments according to the present
invention include without limitation dosages that are effective to
achieve the described phenomena.
[0056] The therapeutic agent or agents may be linked by occlusion
in the matrices of the polymer coating, bound by covalent linkages
to the coating or to a biodegradable stent, or encapsulated in
microcapsules that are associated with the stent and are themselves
biodegradable. Within certain embodiments, the therapeutic agent or
agents are provided in noncapsular formulations such as
microspheres (ranging from nanometers to micrometers in size),
pastes, threads of various size, films and sprays that are applied
to the stent.
[0057] Within certain aspects, the biodegradable stent and/or
coating is formulated to deliver the therapeutic agent or agents
over a period of several hours, days, or, months. For example,
"quick release" or "burst" coatings are provided that release
greater than 10%, 20%, or 25% (w/v) of the therapeutic agent or
agents over a period of 7 to 10 days. Within other embodiments,
"slow release" therapeutic agent or agents are provided that
release less than 10% (w/v) of a therapeutic agent over a period of
7 to 10 days. Further, the therapeutic agent or agents of the
present invention preferably should be stable for several months
and capable of being produced and maintained under sterile
conditions.
[0058] Within certain aspects, therapeutic coatings may be
fashioned in any thickness ranging from about 50 nm to about 3 mm,
depending upon the particular use. Alternatively, such compositions
may also be readily applied as a "spray", which solidifies into a
film or coating. Such sprays may be prepared from microspheres of a
wide array of sizes, including for example, from 0.1 .mu.m to 3
.mu.m, from 10 .mu.m to 30 .mu.m, and from 30 .mu.m to 100
.mu.m.
[0059] The therapeutic agent or agents of the present invention
also may be prepared in a variety of "paste" or gel forms. For
example, within one embodiment of the invention, therapeutic
coatings are provided which are liquid at one temperature (e.g.,
temperature greater than 37.degree. C., such as 40.degree. C.,
45.degree. C., 50.degree. C., 55.degree. C. or 60.degree. C.), and
solid or semi-solid at another temperature (e.g., ambient body
temperature, or any temperature lower than 37.degree. C.). Such
"thermopastes" readily may be made utilizing a variety of
techniques. Other pastes may be applied as a liquid, which solidify
in vivo due to dissolution of a water-soluble component of the
paste. The solidified polymer/drug will stick to the vessel wall.
Drug in the polymer will elute slowly over time to treat the vessel
wall.
[0060] Within yet other aspects, the therapeutic compositions of
the present invention may be formed as a film. Preferably, such
films are generally less than 5, 4, 3, 2, or 1 mm thick, more
preferably less than 0.75 mm, 0.5 mm, 0.25 mm, or, 0.10 mm thick.
Films can also be generated of thicknesses less than 50 .mu.m, 25
.mu.m or 10 .mu.m. Such films are preferably flexible with a good
tensile strength (e.g., greater than 50, preferably greater than
100, and more preferably greater than 150 or 200 N/cm.sup.2), have
good adhesive properties (i.e., adhere to moist or wet surfaces),
and have controlled permeability.
[0061] Within certain embodiments, the therapeutic compositions may
also comprise additional ingredients such as surfactants (e.g.,
pluronics, such as F-127, L-122, L-101, L-92, L-81, and L-61).
[0062] In one embodiment, the coating is coated with a physical
barrier. Such barriers can include inert biodegradable materials
such as gelatin, poly(lactide-co-glycolide)/methyl-poly(ethylene
glycol) (PLGA/MePEG) film, poly(lactic acid) (PLA), or polyethylene
glycol among others. In the case of PLGA/MePEG, once the PLGA/MePEG
becomes exposed to blood, the MePEG will dissolve out of the PLGA,
leaving channels through the PLGA to underlying layer of
biologically active substance (e.g., poly-1-lysine, fibronectin, or
chitosan), which then can initiate its biological activity.
[0063] Protection of the therapeutic coating also can be utilized
by coating the surface with an inert molecule that prevents access
to the active site through steric hindrance, or by coating the
surface with an inactive form of the biologically active substance,
which is later activated. For example, the coating further can be
coated readily with an enzyme, which causes either release of the
therapeutic agent or agents or activates the therapeutic agent or
agents. Indeed, alternating layers of the therapeutic coating with
a protective coating may enhance the time-release properties of the
coating overall.
[0064] Another example of a suitable second coating is heparin,
which can be coated on top of therapeutic agent-containing coating.
The presence of heparin delays coagulation. As the heparin or other
anticoagulant dissolves away, the anticoagulant activity would
stop, and the newly exposed therapeutic agent-containing coating
could initiate its intended action.
[0065] The stent can be made in a layer structure (laminate) with
either biodegradable or non-biodegradable materials, for example as
shown in FIGS. 7A and 7B.
[0066] In another strategy, the stent can be coated with an
inactive form of the therapeutic agent or agents, which is then
activated once the stent is deployed. Such activation could be
achieved by injecting another material near the aneurysmal sac
after the stent is deployed. Or, the activating agent could be
delivered anywhere in the vascular system such that its
distribution and diffusion would reach the inactive form of the
therapeutic substances and activate it.
[0067] Alternately, the implantation of the stent of the type
described above could be followed by implantation of an
endovascular stent graft exclusion device. In this iteration, the
stent material could be coated with an inactive form of the
therapeutic agent or agents, applied in the usual manner and
deployed as described above. Prior to the deployment of the aortic
segment of an abdominal aortic aneurysms (AAA) exclusion stent
graft device, an activation substance delivery catheter would be
placed within the aneurysm sac via an iliac artery, or via an upper
limb vessel such as a brachial artery, or via the same vessel as
the AAA device is to be inserted. Once the AAA stent graft is
deployed, this catheter will be inside the aneurysm sac, but
outside the AAA stent graft. The AAA stent graft would then be
deployed in the usual manner. Once the stent graft is fully
deployed, excluding the aneurysm, the activating substance is
injected into the aneurysm sac around the outside of the AAA stent
graft to cause activation of the therapeutic agent or agents. The
activation substance delivery catheter would then be removed to
leave the drug coated stent activated inside the aneurysmal sac
excluded by the AAA stent graft.
[0068] While the present invention has been described with
reference to specific embodiments, it should be understood by those
skilled in the art that various changes may be made and equivalents
may be substituted without departing from the true spirit and scope
of the invention. In addition, many modifications may be made to
adapt a particular situation, material, or process to the
objective, spirit and scope of the present invention. All such
modifications are intended to be within the scope of the
invention.
[0069] All references cited herein are to aid in the understanding
of the invention, and are incorporated in their entireties for all
purposes.
* * * * *